iMedPub Journals

2015

INTERNATIONAL ARCHIVES OF MEDICINE

http://journals.imed.pub

Section: Internal Medicine & Hospital Medicine

ISSN: 1755-7682

Paroxysmal Nocturnal
Hemoglobinuria: Report
of Suboptimal Response
to the Use of Eculizumab
CASE REPORT

Abstract
Introduction: The Paroxysmal Nocturnal Hemoglobinuria (PNH) is
an acquired clonal disorder of one or more stem cells of hematopoietic lineage. It is characterized as a chronic hemolytic anemia in
which there is a persistent intravascular hemolysis which is subject to
exacerbations due to production of subpopulations of erythrocytes,
platelets and granulocytes hypersensitive to complement. Furthermore
there has been a high tendency to thrombosis. The anti-complement
therapy is the only recognized treatment for this condition. We report
a case of PNH with suboptimal response to anti-complement therapy.

Vol. 8 No. 155

doi: 10.3823/1754

Ricardo Parente Garcia

Vieira1, Lucas Parente
Alencar1, George Nilton
Nunes Mendes2, Natlia
Parente Alencar2,
Francisco Rmulo Patrcio
de S1, Hermes Melo
Teixeira Batista1,3, Jully
Graziela Coelho Campos
Couto2, Jos Lucas Souza
Ramos4, Thiskara Ramile
Caldas Leite4, Italla Maria
Pinheiro Bezerra3, Luiz
Carlos de Abreu3
1 1 Hospital Regional do Cariri. Juazeiro do
Norte-Ce/Brazil
2 Faculty of medicine Juazeiro do Norte-Ce/
Brazil
3 Laboratory of design and Scientific writing
of the FMABC. Santo Andr- So Paulo/
Brazil
4 Faculty of Juazeiro do Norte-Ce/Brazil

Contact information:
Ricardo Parente Garcia Vieira

Method: This is one case report, obtained through data from medical records of a reference hospital, located in the city of Barbalha,
Cear, Brazil.

ricardo.pgv@gmail.com

Case report: Patient with PNH, with typical clinical features, however nonspecific from the onset of the clinical picture, especially marked
by signs and symptoms of anemic syndrome (asthenia, lethargy palpitations, paleness). Showed present hemolysis markers and negative
Coombs test. The flow cytometry closed the diagnosis of paroxysmal
nocturnal hemoglobinuria and there was the initiation of the anticomplement therapy using the drug called eculizumab. After one year
of treatment, the patient persists with anemia and sporadic episodes
of hemoglobinuria, as well as present hemolysis markers. However,
she remains free of thromboembolic events and without need for
transfusion.

Under License of Creative Commons Attribution 3.0 License

Keywords
paroxysmal nocturnal
hemoglobinuria, eculizumab,
complement system

This article is available at: www.intarchmed.com and www.medbrary.com

INTERNATIONAL ARCHIVES OF MEDICINE

Section: Internal Medicine & Hospital Medicine

ISSN: 1755-7682

2015
Vol. 8 No. 155
doi: 10.3823/1754

Conclusion: The PNH is a rare pathology with high morbidity and

mortality if not treated. The anti-complement therapy with eculizumab offers great chance of long-term control of the most harmful
consequences of the disease.

Introduction
The Paroxysmal Nocturnal Hemoglobinuria (PNH)
is an acquired clonal disorder of one or more stem
cells of hematopoietic lineage characterized as a
chronic hemolytic anemia by persistent intravascular hemolysis and subject to exacerbations due to
the production of subpopulations of erythrocytes,
platelets and granulocytes hypersensitive to complement. The PNH is a rare hematologic disorder. The
prevalence of 1-1.5 cases per million of residents is
estimated. There is no evidence of hereditary susceptibility, occurring in all social classes and both
sexes. The diagnosis is usually made around the
third to fifth decade of life although it can occur at
any age. The most common initial clinical symptoms
of the patients with PNH is characterized by fatigue
due to anemia that is present in most cases and
can be of varying degrees. The hemoglobinuria is
reported as initial presentation in only a minority of
the cases. Patients can also refer nausea, abdominal
pain, dysphagia, and esophageal spasms resulting
from acute intravascular hemolysis outbreaks. The
most common physical findings in patients with
PNH include paleness and jaundice, the latter being
generally mild or even absent.
All patients with an acquired chronic hemolytic anemia with direct negative anti-globulin test
(Coombs), particularly if they have hemoglobinuria
and patients with myelodysplastic syndromes and
aplastic anemia should be evaluated, regardless
if there is the presentation of clinically manifest-

ed hemolysis, since we can be facing a subclinical

PNH. The Flow Cytometry is currently the method
of choice for the investigation of PNH, as it is widely
available and is able to assess with great sensitivity
and specificity the expression of proteins anchored
by glycosylphosphatidylinositol (GPI).
The conventional treatment in patients with PNH
is based on hemotherapeutic and clinical support,
however in recent years there was great pharmacological breakthrough with the advent of a drug
called eculizumab. The degree of hemolysis that
these patients are exposed to varies greatly between
patients and are related to the size of the PNH clone
and the degree of bone marrow failure: some patients with PNH present recurrent or persistent episodes of hemolysis and hemoglobinuria, becoming
dependent of blood transfusions and may present
episodes of thrombosis (especially in the abdominal
venous system), main cause of death in individuals
with this disease. Others, present rare episodes of
hemoglobinuria, controlled hemolytic anemia and
rarely require some transfusion support. The only
healing treatment in PNH is the transplantation of
hematopoietic stem cells, but this is associated with
considerable morbidity and mortality and is indicated only in specific cases.
In this sense, understanding the difficulty of establishing a proper diagnosis because of the low
incidence of this pathology, associated with its importance in the correct management of patients
with PNH, this study aimed to report a case of PNH
with suboptimal response to the anti-complement
therapy.
This article is available at: www.intarchmed.com and www.medbrary.com

INTERNATIONAL ARCHIVES OF MEDICINE

Section: Internal Medicine & Hospital Medicine

ISSN: 1755-7682

Case Report
Female patient, 37 years old, presenting clinical
picture mainly marked by signs and symptoms of
the anemic syndrome that started up about one
year after the initial treatment (asthenia, lethargy
palpitations, pallor) and episodes of dark urine. After the physical examination, we could not observe
changes worthy of notification other than moderate
mucocutaneous pallor and mild jaundice. Laboratory
evaluation revealed anemia (Hb 7.8 g/dl), mild leukopenia, and normal platelet count. There was the
presence of levels of lactate dehydrogenase (LDH)
increased by about 10 times the upper limit of normal, reticulocytosis(7%), indirect hyperbilirubinemia
with negative direct anti-globulin test (COOMBS).
Because the study is about a young patient without
comorbidities and with clinical picture marked by
acute and recurrent episodes of intravascular hemolysis, the diagnostic possibility of paroxysmal nocturnal hemoglobinuria has been suggested which
was confirmed by flow cytometry, which revealed
a PNH clone of 45% in granulocytes. She remained
about six months using folic acid and prednisone
at low doses and in this period the patient evolved
with need of monthly red blood cells transfusion
and several episodes of hemoglobinuria. After this
period the national public health system released
the use of anti-complement therapy with the drug
eculizumab. After about 1 year of anti-complement
therapy with eculizumab the patient remains free
of transfusions and thromboembolic events; however the hemoglobin levels remains between 7-8g/
dl, elevated LDH at about 2 times the upper limit
of normal and reticulocytosis.

Discussion
The present study reports the case of a patient
with PNH, presenting typical clinical features, but
nonspecific from the onset of the clinical picture,
Under License of Creative Commons Attribution 3.0 License

2015
Vol. 8 No. 155
doi: 10.3823/1754

marked especially by signs and symptoms of the

anemic syndrome (asthenia, lethargy palpitation,
pallor) and the presence of dark urine. The hemoglobinuria, classic sign of PNH which is present in a
minority of the cases, has been reported by the patient. This characteristic finding, however, is present
only in the initial report of a minority of patients but
when questions are asked directed about the presence of dark urine, this change would be found
more often. [1]
PNH may be present in its classical form in which
there is the presence of clinical evidences of intravascular hemolysis without evidence of other manifestations caused by abnormalities in the bone marrow
or can occur associated with another specific bone
marrow disorder such as bone marrow aplasia, and
myelodysplastic syndrome. [2]
Approximately 29-44% of patients with PNH have
at least one episode of thromboembolism during
the evolution of their disease. This complication is
also responsible for high mortality rates, accounting
for approximately 40-67% of the causes of death
in individuals with such hematological disease. [3]
Thromboembolic phenomena can occur anywhere, but the main sites involved are the supra-hepatic and cerebral veins. Most patients have such
phenomena in the first five years after the diagnosis. After three years of clinical follow-up, the patient of the study never showed clinically manifested
thromboembolic events. After careful review of the
case, it was observed that the patient had positive
markers of hemolysis (very high LDH, indirect hyperbilirubinemia, reticulocytosis) and nonreactive direct
Coombs. [3,4,5]
Due to the presence of hemolytic anemia of unknown cause, there was the decision to investigate
the possibility of paroxysmal nocturnal hemoglobinuria. The diagnostic investigation proceeded with
the request of a Flow Cytometry (FCM) gold standard test for diagnosis of the PNH. The FCM uses
antibodies against the GPI anchored proteins, and
the antibodies there are more utilized are the An-

INTERNATIONAL ARCHIVES OF MEDICINE

Section: Internal Medicine & Hospital Medicine

ISSN: 1755-7682

ti-CD55 and Anti-CD59. The test results showed

that the patient had populations of negative granulocytes for CD55 and CD59 which supports and
seals the diagnosis of PNH. [6]
The basic treatment for patients with PNH consisted of hemotherapeutic support, folate replacement and use of corticosteroids, until the approval
of the anti-complement therapy. The patient presented repeated episodes of intravascular hemolysis
which led to the need of monthly blood transfusions. The only healing treatment consists of the
transplant of hematopoietic stem cells. However,
this therapeutic modality has considerable morbidity and mortality rates and should only be indicated
in selected cases. The eculizumab is a humanized
monoclonal antibody directed against the C5 fraction of the terminal complement. It is highly effective in reducing intravascular hemolysis, reducing or
even abolishing the need for blood transfusions in
patients with PNH and dramatically reducing the
incidence of thromboembolic events. The patient
from this case is currently completing one year of

2015
Vol. 8 No. 155
doi: 10.3823/1754

use of the drug eculizumab. In this period she remained free of transfusions and had no thromboembolic events. She remains with anemia of mild to
moderate intensity and sporadic episodes of hemoglobinuria. Though admittedly effective, the high
cost is a limiting factor for the use of Eculizumab in
developing countries. [6,7]

Conclusion
The PNH is a rare pathology with high morbidity
and mortality if not treated. The anti-complement
therapy with eculizumab offers great chance of
long-term control of the most harmful consequences of the disease (thromboembolic events, need
for transfusion). We report a case of suboptimal
response to eculizumab (persistence of anemia and
hemoglobinuria crisis). However, the same therapy
obtained great success in controlling the transfusion need and the occurrence of thromboembolic
events.

This article is available at: www.intarchmed.com and www.medbrary.com

INTERNATIONAL ARCHIVES OF MEDICINE

Section: Internal Medicine & Hospital Medicine

ISSN: 1755-7682

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Under License of Creative Commons Attribution 3.0 License

2015
Vol. 8 No. 155
doi: 10.3823/1754

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